IDH-Tau-EGFR triad defines the neovascular landscape of diffuse gliomas by controlling mesenchymal differentiation

Abstract

Classification of gliomas as wild-type or mutant IDH1/2 tumors has profound clinical implications. However, how these two groups of gliomas progress, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau is epigenetically induced by mutant IDH1/2, whereas is almost absent from tumors with EGFR/PTEN mutations. Moreover, Tau (MAPT) expression is inversely correlated with overall survival in EGFR-amplified gliomas. Using orthotopic EGFR-related models, we have observed that Tau overexpression or microtubule stabilizers impair the mesenchymal transformation of glioma cells, with profound changes in tumor vasculature and a significant decrease in tumor burden. However, epithelial-to-mesenchymal transformed EGFR-mutant cells, acting as pericytes, induce neo-vasculogenesis and favor aggressive glioma growth, a process that is no longer sensitive to Tau. Altogether our data indicate that the genomic background controls glioma aggressiveness by modifying the vascular microenvironment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/541326v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1c4b33forg.highwire.dtl.DTLVardef@d3f636org.highwire.dtl.DTLVardef@1c957c1org.highwire.dtl.DTLVardef@1a04a0d_HPS_FORMAT_FIGEXP M_FIG C_FIG